Mammary and endometrial cancer are among the leading causes of premature death in North American women. Approximately one in nine women in this country will develop breast cancer during their lifetime and the incidence of mammary cancer has been increasing. Over 150,000 new cases of endometrial cancer are diagnosed worldwide each year. Epidemiology studies have clearly demonstrated that both mammary and endometrial cancer share a common set of risk factors including: early age at menarche, late age at menopause, obesity, parity and increased exposure to unopposed estrogen. A high percentage of early stage mammary tumors are estrogen receptor positive (ER+), and many of these patients respond to antiestrogen or endocrine therapy with drugs such as tamoxifen which has now been successfully used for treatment of several million women with breast cancer. Unfortunately, resistance to tamoxifen can develop in some patients and there is now increasing concern that long term use of this drug increases the risk for endometrial cancer. Therefore, it is imperative to develop new drugs which can be used alone or in combination therapy (e.g. with tamoxifen) for treatment of hormone-dependent tumors. Our studies have identified alternate-substituted alkyl PCDFs as a new mechanism-based class of antiestrogens which block estrogen-induced mammary and endometrial cell/tumor growth via crosstalk between the ER and Ah receptor signaling pathways. Based on results of previous studies, the antitumorigenic activities of selected alkyl PCDFs will be thoroughly investigated in the DMBA-induced rat mammary tumor model (Aim 1) and athymic nude mice bearing breast cancer cell xenografts (Aim 2). Aim 3 will focus on their inhibition of endometrial cancer growth in rodent models and Aim 4 will determine the important interaction of tamoxifen and alkyl PCDFs in both mammary and endometrial cancer models. These studies will also determine tissue-specific inhibition of tamoxifen-induced estrogenic responses in the uterus, bone and on serum cholesterol levels by alkyl PCDFs. Preliminary studies indicate that alkyl PCDFs block the effects of tamoxifen only in the uterus. Thus the proposed studies will define a new mechanism-based class of antiestrogens that can be used alone or in combination with tamoxifen for treatment of breast and endometrial cancer.